Since the early 1950's, physiologists and clinicians have recognized that the hypothalamus of the brain controls all the secretory functions of the adenohypophysis. This control is neurohumoral, with specialized neurosecretory neurons in the hypothalamus producing special polypeptides, the effect and role of each of which is to trigger acutely and chronically the secretion of each pituitary hormone. To this day, a hypothalamic releasing factor has been characterized for the pituitary hormones thyrotropin and prolactin (the tripeptide TRF), for the pituitary gonadotropins luteinizing hormone and follicle stimulating hormone (the decapeptide LRF, LH-RH, GnRH or Gn-RF) and for the pituitary hormones .beta.-endorphin and adrenocorticotropin (the 41-amino acid polypeptide CRF). In addition, an inhibitory factor has been characterized: hypothalamic somatostatin inhibits, at the pituitary level, the secretion of growth hormone. Each of these hypothalamic releasing factors and somatostatin have been reproduced by total synthesis, and many analogs of the native structures have been synthesized, some with far greater activity than the natural compounds.
To this day, a corresponding hypothalamic releasing factor for the pituitary growth hormone or somatotropin has not been characterized, even though there has been extensive physiological and clinical evidence for its existence. One of the major problems in the isolation and characterization of the hypothalamic growth hormone releasing factor (hereinafter GRF) is that the active peptide appears to be present in each hypothalamic fragment in infinitesimal amounts which we believe to be of the order of 50-150 femtomoles. This is far less than anything ever calculated for the other hypothalamic releasing factors. In keeping with this statement is the corollary that hypothalamic GRF is of extremely high potency.
Another major problem in the isolation of hypothalamic GRF has been the presence in hypothalamic extracts of very large amounts of somatostatin which of course prevent or would give aberrant results in any attempted bioassay. Over the last few years, several laboratories have claimed to have isolated and characterized the hypothalamic GRF; all these claims were dealing with artifacts as recognized later by the authors (Schally, A. V. S. et al. J. Biol. Chem. 246, 6647, 1971; Veber D. F. et al., Biochem. Biophys. Res. Commun. 45, 235, 1971). Such incorrect claims can be explained in part, by the difficulty of the bioassays involved in assessing release of growth hormone.